Asymmetric epoxidation reaction

ABSTRACT

An optically active manganese complex of the formula I or I&#39;: ##STR1## wherein R 1 , R 2 , R 3 , and R 4  independently represent hydrogen atom, C 1  -C 4  alkyl group, phenyl group which may be substituted by a halogen atom, C 1  -C 4  alkyl group, C 1  -C 4  alkoxyl group, cyano group or nitro group; and any two of R 1 , R 2 , R 3  and R 4  together form the C 4  -C 8  ring, X -   represents a counter anion which may form a salt, Y represents hydrogen atom, halogen atom, C 1  -C 4  alkyl group, C 1  -C 4  alkoxyl group, nitro group or cyano group, R represents hydrogen atom, C 1  -C 4  alkyl group, phenyl group which may be substituted by halogen atom, C 1  -C 4  alkyl group or C 1  -C 4  alkoxyl group, or substituted silyl group and a process for producing epoxy compounds using the complex as a catalyst.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relate to a process for producing an opticallyactive epoxy compound which is an important intermediate in synthesis ofan optically active medicines including benzopyran compound, etc., forthe treatment of hypertension, asthma, etc.

2. Description of the Prior Art

One of the most general methods in case that an epoxy compound is usedfor preparing optically active medicines is a separation of diastereomerat a further proceeded stage (e.g., to treat amino-alcohol compoundobtained by reacting the epoxy compound with ammonia. It is exemplifiedby the optical resolution of pyranobenzoxadiazole compounds described inJapanese Patent Application Laid-open No. 141286/1991, EP 409165, andU.S. Pat. No. 5,097,037, and also by the synthesis of optically activeindene oxide described in J. Med. Chem., 35, 1685-1701 (1992). There isanother method which involves the step of making a halohydrin compound(as a precursor of an epoxy compound) into its derivatives andconducting the separation of the diastereomer on it at that step, orwhich resorts to the stereoselectivity of an enzyme. An example is theoptical resolution of benzopyran compounds, which is described inCirculation Research, 62, 4, 679-686 (1988). The foregoing two methods,however, suffer a serious economical disadvantage that as they separateracemic mixture, enantiomer which is not used become completely wasted.

There has recently been found a new process for synthesis which employsan optically active manganese complex as an asymmetric catalyst. Thisprocess is attracting attention because of its ability to yieldoptically active epoxy compounds effectively. Examples of the asymmetriccatalyst are given by Jacobsen, et. al. in J. Am. Chem. Soc., 113,7063-7064, (1991) and also by Katsuki in Japanese Patent ApplicationLaid-open No. 301878/1993 and European Patent Laid-open No. 535377.Unlike the separation of racemic mixture, this process solved theproblem that enantiomer which is not used becomes wasted. Therefore, itaffords high chemical and optical yields if appropriate olefins areselected as the starting material. However, the catalysts reported sofar are not satisfactory for the production of every optically activeepoxy compound. Active researches are under way for further improvement.

After the present inventors have conducted their intensive researches,they have found out a process for producing optically active epoxycompounds by using olefin compounds which do not have functional groupcoordinating with metals such as hydroxy group at the neighbour of adouble bond. (Said olefin compounds are hereinafter referred to as"unfunctionalized olefin compound" or "olefin compound having noprecoordinating functional group".)

SUMMARY OF THE INVENTION

The present inventors have intensively investigated a process forproducing an optically active epoxy compound of the formula III:##STR2## wherein R⁵ and R⁶ independently represents a hydrogen atom,cyano group, nitro group, amino group which may be protected by anacetyl group or the like, halogen atom, C₁ -C₄ alkyl group, C₁ -C₄alkoxyl group, halo-C₁ -C₄ alkyl group, carboxyl group, formyl group, C₁-C₄ alkanoyl group, aroyl group, halo-C₁ -C₄ alkanoyl group, carbamoylgroup, C₁ -C₄ alkylsulfinyl group, arylsulfinyl group, C₁ -C₄alkylsulfonyl group, arylsulfonyl group, sulfonamide group, or mono- ordi-C₁ -C₄ alkylsulfoamide group, or if R⁵ and R⁶ are at the orthoposition, R⁵ and R⁶, together with the linking ring, form a group of theformula: ##STR3## wherein n is 0 or an integer of 1, R⁷ representshydrogen atom, C₁ -C₄ alkyl group or C₁ -C₄ alkoxyl group, R⁸ representsC₁ -C₄ alkyl group or C₁ -C₄ alkoxyl group, R⁷ and R⁸ together form thegroups of the formulae: ##STR4## wherein R⁹, R¹⁰, R¹¹ and R¹²independently represent a hydrogen atom or C₁ -C₄ alkyl group, and theabsolute configuration of the carbon atoms which are marked withasterisks (*) means R or S, from an olefin compound of the formula II:##STR5## where in R⁵, R⁶, R⁷ and R⁸ have the same meanings as definedabove, as a starting material. As a result, it has been found that it ispossible to produce the intended optically active epoxy compound of theformula III in high asymmetric yields, by using, as an asymmetriccatalyst, an optically active manganese complex of the formula I or I':##STR6## wherein R¹, R², R³, and R⁴ independently represent hydrogenatom, C₁ -C₄ alkyl group, phenyl group which may be substituted by ahalogen atom, C₁ -C₄ alkyl group, C₁ -C₄ alkoxyl group, cyano group ornitro group; and any two of R¹, R², R³ and R⁴ together form the C₄ -C₈ring, X⁻ represents a counter anion which may form a salt, Y representshydrogen atom, halogen atom, C₁ -C₄ alkyl group, C₁ -C₄ alkoxyl group,nitro group or cyano group, R represents hydrogen atom, C₁ -C₄ alkylgroup, phenyl group which may be substituted by halogen atom, C₁ -C₄alkyl group or C₁ -C₄ alkoxyl group, or substituted silyl group. Thepresent invention has been completed on the basis of this finding.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The optically active manganese complex [I] or [I'] has substituentgroups R¹, R², R³ and R⁴, each of which may be hydrogen atom, C₁ -C₄alkyl group or phenyl group. The C₁ -C₄ alkyl group may be any one ofmethyl group, ethyl group, normal-propyl group, isopropyl group,normal-butyl group, isobutyl group, secondary butyl group and tertiarybutyl group. The phenyl group may be substituted by any of fluorineatom, chlorine atom, bromine atom, methyl group, ethyl group,normal-propyl group, isopropyl group, normal-butyl group, isobutylgroup, secondary butyl group, tertiary butyl group, methoxy group,ethoxy group, normal-propoxy group, isopropoxy group, normal-butoxygroup, isobutoxy group, secondary butoxy group, tertiary butoxy group,cyano group and nitro group. Of these substituent groups, any ofhydrogen atom, ethyl group, tertiary butyl group, phenyl group and3,5-dimethylphenyl group are preferable.

Any two of the substituents R¹, R², R³ and R⁴ may together form a C₄ -C₈ring such as cyclobutane, cyclopentane, cyclohexane, cycloheptane andcyclooctane.

The group R includes a phenyl group, fluorophenyl group, chlorophenylgroup, bromophenyl group, tolyl group, ethylphenyl group, tertiarybutylphenyl group, 3,5-dimethylphenyl group, methoxyphenyl group (ofortho, meta and para isomers), hydrogen atom, methyl group, ethyl group,isopropyl group, normal-propyl group, normal-butyl group, isobutylgroup, secondary butyl group, tertiary butyl group and substituted silylgroup.

Examples of the substituted-silyl group include trimethylsilyl,triethylsilyl, tri-normal-propylsilyl, triisopropylsilyl,tri-normal-butylsilyl, triisobutylsilyl, tri-normal-hexylsilyl,dimethylethylsilyl, dimethyl-normal-propylsilyl,dimethyl-normal-butylsilyl, dimethylisobutylsilyl,dimethyl-tertiary-butylsilyl, dimethyl-normal-pentylsilyl,dimethyl-normal-octylsilyl, dimethylcyclohexylsilyl,dimethylthexylsilyl, dimethyl-2,3-dimethylpropylsilyl,dimethyl-2-(bicycloheptyl)silyl, dimethylbenzylsilyl,dimethylphenylsilyl, dimethyl-para-tolylsilyl, dimethylflophemesylsilyl,methyldiphenylsilyl, triphenylsilyl, diphenyl-tertiary butylsilyl,tribenzylsilyl, diphenylvinylsilyl, diphenyl-normal-butylsilyl andphenylmethylvinylsilyl.

Example of Y includes a hydrogen atom, halogen atom such as fluorineatom, chlorine atom and bromine atom, methyl group, ethyl group,normal-propyl group, isopropyl group, normal-butyl group, isobutylgroup, secondary butyl group, tertiary butyl group, methoxy group,ethoxy group, normal propoxy group, isopropoxy group, normal-butoxygroup, isobutoxy group, secondary butoxy group, tertiary butoxy group,nitro group and cyano group.

The optically active maganise complex [I] or [I'] can form a salttogether with various kinds of the counter anion (X⁻) as a manganesewhich is a metal center can be monovalent to pentavalent oxidized state.The examples of the counter anion include monovalent OH⁻, F⁻, Cl⁻, Br⁻,I⁻, CH₃ CO⁻, PF₆ ⁻, ClO₄ ⁻ and BF₄ ⁻ ions; divalent CO₃ ²⁻ and SO₄ ²⁻ions; and trivalent PO₄ ³⁻ ion. All of these salts can be used asasymmetric catalyst of the present invention.

The folloing is the typical synthesis examples of the optically activemanganese complex [I] or [I'].

Scheme 1 shows a synthesis method of only the compound of the formula[I] wherein R¹ =R³ =R=Ph (phenyl group), R² =R⁴ =H and X=CH₃ CO₂ ⁻.Since the compound [I] and the compound [I'] are in the relation ofantipode to each other, it is enough to simply replace the opticallyactive binaphthol and diamine as the starting materials with ones thosehaving the opposite configuration in order to synthesize the compound[I'] wherein R¹ =R³ =Ph (phenyl group), R² =R⁴ =H, and X=CH₃ CO₂ ⁻.

According to Scheme 1, the synthesis consists of the steps of (a)reacting an optically active binaphthol having the molecular asymmetrywith N-phenyltrifluoromethanesulfonimide in the presence of collidine,thereby converting one of the hydroxyl groups as a triflate; (b)substituting the triflate with a phenyl Grignard reagent, usingchloro[1,2-bis(diphenylphosphino)ethane]nickel (II) as a catalyst; (c)conducting methoxymethylation with chloromethyl methyl ether under basicconditions; (d) conducting lithiation with tertiary-butyl lithium; (e)conducting formylation with dimethylformamide; and (f) conductingdemethoxylmethylation with trimethylsilyl bromide, thereby yielding asalicyl aldehyde compound. The synthesis of a compound in which R groupis different can be prepared by changing the kind of Grignard reagentsin the step (b). As the diamine compounds which are the other startingmaterial, marketed ones are used.

Scheme 2 shows a case of the synthesis of a noncommercial diaminewherein R¹ =R³ =3,5-dimethylphenyl group and R² =R⁴ =H. Namely, Scheme2, the synthesis consists of the steps of (g) converting3,5-dimethylbenzoic acid into alcohol by reduction with lithium aluminumhydride; (h) converting it into aldehyde by oxidation with manganesedioxide; (i) performing dimerization by the aid of titaniumtetrachloride and zinc dust; (j) converting the dimer into a high-purityoptically active diol by Sharpless asymmetric dihydroxylation reaction,using osmium tetraoxide having hydroquinidine 4-chlorobenzoate as theasymmetric source; (k) mesylating the hydroxyl group with mesyl chlorideunder basic conditions; (1) performing the substitution reaction withsodium azide; and (m) reducing the azide with lithium aluminum hydride,thereby yielding the intended diamine compound. The foregoing procedureis not limitative because there are several ways of synthesis accordingto the kinds of the substituents.

The salicyl aldehyde compound and the diamine compound obtained asdescribed above are mixed in a solvent to give an imine compound.Examples of the solvent include alcohols such as ethanol and methanol,nitriles such as acetonitrile and propionitrile, halogenatedhydrocarbons such as dichloromethane and chloroform, aromatichydrocarbons such as benzene and toluene, ethers such as tetrahydrofuranand diethyl ether, and aliphatic hydrocarbons such as hexane andheptane. Of these solvents, ethanol, methanol, acetonitrile,dichloromethane, and toluene are preferable. If necessary, the solventmay be used in combination with more than equimolar amount ofdehydrating agent, such as anhydrous magnesium sulfate, boric anhydride,and Molecular Sieves. Alternatively, the solvent may be dehydrated byazeotropic dihydration. The reaction temperature is not specificallylimited, but it ranges from -20° C. to the boiling point of the solventused, preferably, from 0° C. to 50° C. It is not always necessary toseparate the imine from the reaction mixture; it may remain in thereaction mixture as a following procedure in the synthesis of themanganese complex.

The thus obtained imine compound is dissolved or suspended in an alcoholsolvent such as ethanol and methanol, a nitrile solvent such asacetonitrile and propionitrile, and a halogenated hydrocarbon solventsuch as dichloromethane and chloroform. Manganese acetate in an amountof 0.5-10 molar equivalent, preferably 0.8-2 molar equivalent, is addedto the solution or suspension. Reaction is carried out in the presenceof oxygen to give the intended optically active manganese complex [I].If necessary, the CH₃ CO₂ ⁻ ion may be replaced by Cl⁻, PF₆ ⁻, or anyother anion. Replacement by the Cl⁻ ion may be accomplished by addingmore than equimolar amount of lithium chloride to the reaction mixture.Examples of the preferred solvent include ethanol, methanol,acetonitrile and dichloromethane. The reaction temperature is notspecifically limited; it may range from -20° C. to the boiling point ofthe solvent used. The preferred reaction temperature ranges from 0° C.to 50° C. Oxygen required for the reaction may be supplied by blowing alarge excess of air or oxygen gas into the reaction mixture or bystirring, with the reaction system open to the atmosphere.

Scheme 3 shows the synthesis of the optically active manganese complex[I] wherein R¹ =R³ =Ph (phenyl group), R² =R⁴ =H, and X=CH₃ CO₂ ⁻ inwhich a diamine compound is (1S, 2S)-1,2-diphenyl-1,2-ethanediamine.##STR7## wherein Ph represents phenyl, Tf₂ NPh representsN-phenyltrifluoromethanesulfonimide, PhMgBr represents phenyl magnesiumbromide, NiCl₂ (dppe) representschloro[1,2-bis(diphenylphosphino)ethane]nickel (II), MOMCl representschloromethyl methyl ether, (i-Pr)₂ NEt represents diisopropylethylamine,THF represents tetrahydrofuran, DMF represents dimethylformamide, TMSBrrepresents trimethylsilyl bromide, LAH represents lithium aluminumhydride and Et₂ O represents diethyl ether.

The following description is about the concrete process for asymmetricepoxidation. ##STR8##

Asymmetric catalyst, namely, the optically active manganese complex [I]or [I'] is used in the range of, namely, from 0.1 mol % to 100 mol %.preferably from 1 mol % to 5 mol %, based on the mole of the olefincompound [II] as the starting material. Examples of usable oxidizingagents include iodosylbenzene, 2-iodosylbenzoic acid, sodiumhypochlorite, tetrabutylammonium periodate, hydrogen peroxide, oxygen,and air. When iodosylbenzene or 2-iodosylbenzoic acid is used as theoxidizing agent, it is normally used in the range of from 1 equivalentto 10 equivalents, preferably 1 equivalent to 3 equivalents, based onthe olefin compound [II]. When sodium hypochlorite, tetrabutylammoniumperiodate, or hydrogen peroxide is used as the oxidizing agent, it isnormally used in the range of 1 equivalent to 100 equivalents,preferably 3 equivalents to 30 equivalents, based on the olefin compound[II]. Oxidation with a large excess of air or oxygen gas may beaccomplished by blowing air in large excess or oxygen in large excessinto the reaction mixture or by stirring, with the reaction mixture opento the atmosphere.

As a medium for the reaction, there can be used water, acetonitrile,dichloromethane, dichloroethane and a mixture thereof. Especially, whensodium hypochlorite is used as the oxidizing agent, there may bepreferable to use two-phase system such as water and dichloromethane.Also, it can co-exist a component having coordination ability with themanganese complex such as pyridine N-oxide, 4-phenylpyridine N-oxide,lutidine N-oxide or 2-methylimidazole. There is no particular limitationon the quantity of the components to be used.

The reaction is ordinarily carried out at a temperature in the range offrom -50° C. to 50° C., preferably from -20° C. to 25° C.

After the completion of the reaction, the organic solvent is distilledoff under reduced pressure to concentrate the reaction solution and onlyseparated and purified by using a silica gel column chromatography ordistillation to isolate the intended optically active compound [III].The optical purity of the optically compound [III] can be analyzed byoptically active liquid chromatography (using, e.g., Chiralcel OJ mfd.by Daicel Chemical Industries, Ltd.) or optical rotation, underconditions as shown in Examples.

Examples of the olefin compound [II] to which the asymmetric epoxidationreaction of the present invention may be applied include a benzopyranderivative of formula IV: ##STR9## wherein R⁵ and R⁶ independentlyrepresents hydrogen atom, cyano group, nitro group, amino group whichmay be protected by an acetyl group or the like, halogen atom, C₁ -C₄alkyl group, C₁ -C₄ alkoxyl group, halo-C₁ -C₄ alkyl group, carboxylgroup, formyl group, C₁ -C₄ alkanoyl group, aroyl group, halo-C₁ -C₄alkanoyl group, carbamoyl group, C₁ -C₄ alkylsulfinyl group,arylsulfinyl group, C₁ -C₄ alkylsulfonyl group, arylsulfonyl group,sulfonamide group, or mono- or di-C₁ -C₄ alkylsulfonamide group, R⁵ andR⁶ may together form a ring represented by the following formula:##STR10## wherein n is 0 or an integer of 1, R⁹ and R¹⁰ independentlyrepresent hydrogen atom or C₁ -C₄ alkyl group, or an indene derivativeof the formula VI: ##STR11## wherein R⁹ and R¹⁰ have the same meaningsdefined above.

Preferred benzopyran derivatives may be represented by the formula:##STR12## wherein R⁵ and R⁶ independently represents hydrogen atom,cyano group, nitro group, amino group which may be protected by acetylgroup or the like, halogen atom, C₁ -C₄ alkyl group, C₁ -C₄ alkoxylgroup, halo-C₁ -C₄ alkyl group, carboxyl group, formyl group, C₁ -C₄alkanoyl group, aroyl group, halo-C₁ -C₄ alkanoyl group, carbamoylgroup, C₁ -C₄ alkylsulfinyl group, arylsulfinyl group, C₁ -C₄alkylsulfonyl group, arylsulfonyl group, sulfonamide group or mono- ordi-C₁ -C₄ alkylsulfonamide group, and a compound of the formula:##STR13## wherein n is 0 or an integer of 1.

Preferred indene derivative may be represented by the formula: ##STR14##

Any of these derivatives yields the intended epoxy compound whenprocessed as described above. ##STR15##

R⁵ and R⁶ which are the substituents of the compounds of the formulae IVand V independently represent hydrogen atom, cyano group, nitro group,amino group which may be protected by acetyl group or the like, halogenatom, C₁ -C₄ alkyl group, C₁ -C₄ alkoxyl group, halo-C₁ -C₄ alkyl group,carboxyl group, formyl group, C₁ -C₄ alkanoyl group, aroyl group,halo-C₁ -C₄ alkanoyl group, carbamoyl group, C₁ -C₄ alkylsulfinyl group,arylsulfinyl group, C₁ -C₄ alkylsulfonyl group, arylsulfonyl group,sulfonamide group, or mono- or di-C₁ -C₄ alkylsulfonamide group, or R⁵and R⁶, together with the linking ring, form the formula: ##STR16##wherein n is 0 or an integer of 1.

Examples of the protecting group of the amino group include acyl groupssuch as acetyl group, propionyl group, trifluoroacetyl group, andbenzoyl group, alkoxycarbonyl group such as methoxycarbonyl group,ethoxycarbonyl group, tertiary butoxycarbonyl group, tosyl group, andbenzyl group, preferably, acetyl group and tertiary butoxycarbonylgroup.

The halogen atom includes fluorine atom, chlorine atom, bromine atom andiodine atom.

The C₁ -C₄ alkyl group includes methyl group, ethyl group, normal-propylgroup, isopropyl group, normal-butyl group, isobutyl group, secondarybutyl group and tertiary butyl group.

The C₁ -C₄ alkoxyl group includes methoxy group, ethoxy group,normal-propoxy group, isopropoxy group, normal-butoxy group, isobutoxygroup, secondary butoxy group and tertiary butoxy group.

The halo-C₁ -C₄ alkyl group represents any group formed by substitutingthe above-described C₁ -C₄ alkyl group with a halogen atom. It includestrifluoromethyl group, mono-chloromethyl group, pentafluoroethyl group,etc.

The C₁ -C₄ alkanoyl group includes acetyl group and propionyl group.

The aroyl group includes benzoyl group, toluoyl group and naphthoylgroup.

The halo-C₁ -C₄ alkanoyl group includes trifluoroacetyl group,monochloroacetyl group and pentafluoropropionyl group.

The C₁ -C₄ alkyl group in the C₁ -C₄ alkylsulfinyl group, C₁ -C₄alkylsulfonyl group, and mono- and di-C₁ -C₄ alkylsulfonamide is definedas described above. The aryl group in the arylsulfinyl group andarylsulfonyl group includes a phenyl group and tolyl group.

The present invention described above provides a new catalyst to be usedto produce, from an olefin compound having no precoordinating functionalgroup, an optically active epoxy compound useful as an optically activemedicine or an intermediate compound thereof.

The present invention will further be illustrated by examples.

EXAMPLES Referential Example 1

Five compounds (1 to 5) represented by the formulae below were prepared.##STR17## wherein Ph represents phenyl, Tf₂ NPh representsN-phenyltrifluoromethanesulfonimide, PhMgBr represents phenyl magnesiumbromide, NiCl₂ (dppe) representschloro[1,2-bis-(diphenylphosphino)ethane]nickel (II), MOMCl representschloromethyl methyl ether, (i-Pr)₂ NEt represents diisopropylethylamine,THF represents tetrahydrofuran, DMF represents dimethylformamide, TMSBrrepresents trimethylsilyl bromide, DMAP representsdimethylaminopyridine, and Et₂ O represents diethyl ether.

Synthesis of the compound 1

To 4 mL of dichloromethane solution of 286 mg of (R)-(+)-binaphthol (1.0mmol) were successively added 132 μL of 2,4,6-collidine (1.0 mmol), 15mg of dimethylaminopyridine (0.12 mmol), and 357 mg ofN-phenyltrifluoromethanesulfonimide (1.0 mmol). After refluxing fortwelve hours, the reaction mixture was concentrated and the residueswere purified by silica gel column chromatography (eluent: toluene) toobtain the intended compound as colorless crystals. (yield: 378 mg(90%))

Synthesis of the compound 2

To a mixture of 209 mg of the compound 1 (0.5 mmol) and 5.3 mg ofchloro[1,2-bis(diphenylphosphino)ethane]nickel (II) (0.01 mmol) wasslowly added 2.5 mL of phenyl magnesium bromide (in the form of diethylether solution containing 0.8M, 2.0 mmol). After refluxing for one hour,the reactants were cooled to room temperature and the reaction productwas suspended by the addition of a saturated aqueous ammonium chloridesolution. The reaction mixture was extracted with diethyl ether, and theorganic layer was washed successively with a saturated aqueous sodiumhydrogen carbonate solution and a saturated aqueous sodium chloridesolution. The extract was dried over anhydrous magnesium sulfate andthen concentrated. The residues were purified by silica gel columnchromatography (eluent: hexane-toluene=4:6) to obtain the intendedcompound as colorless crystals. (yield: 156 mg (90%))

¹ H NMR (400 MHz): 8.10 (d, J=8.30 Hz, 1H), 7.79 (d, J=8.30 Hz, 1H),7.78 (d, J=9.28 Hz, 2H), 7.72 (d, J=8.79 Hz, 1H), 7.54-7.50 (m, 1H),7.36-7.20 (m, 4H), 7.15-7.04 (m, 7H)

Synthesis of the compound 3

To 4 mL of a dichloromethane solution of 365 mg of the compound 2 (1.1mmol) were successively added 530 μL of diisopropylethylamine (3.0 mmol)and 230 μL of chloromethyl methyl ether (3.0 mmol). After stirring atroom temperature for one day, the reaction mixture was washed withwater, dried over anhydrous sodium sulfate, and then concentrated. Theresidues were purified by silica gel column chromatography (eluent:hexane-diethyl ether=19:1) to obtain the intended compound as coloresscrystals. (yield: 346 mg (83%)

¹ H NMR (90 MHz): 7.00-8.22 (m, 18H), 4.90 (ABq, J=7.07 Hz, 2H), 2.11(s, 3H)

Synthesis of the compound 4

140 mg of the compound 3 (0.36 mmol) was dissolved in 1.5 mL oftetrahydrofuran, and the solution was cooled to -78° C. To the solutionwas added 530 μL of tertiary butyl lithium (in the form of pentanesolution containing 1.5M, 0.8 mmol). After stirring at -78° C. for threehours, 140 μL of dimethylformamide (1.8 mmol) was added. Stirring wascontinued for one hour, with the cooling bath removed. A saturatedaqueous ammonium chloride solution was added to stop the reaction. Thereaction mixture was extracted with diethyl ether. The organic layer waswashed successively with a saturated aqueous sodium hydrogen carbonatesolution and a saturated aqueous sodium chloride solution. The extractwas dried over anhydrous sodium sulfate and then concentrated. Theresidues were purified by silica gel column chromatography (eluent:hexane-diethyl ether=19:1) to obtain the intended compound as yellowishcrystals. (yield: 139 mg (91%))

¹ H NMR (90 MHz): 10.42 (s, 1H), 8.50-7.00 (m, 17H), 4.53 (ABq, J=6.17Hz, 2H), 2.94 (s, 3H)

Synthesis of compound 5

1.5 mL of dichloromethane was added to a mixture of 154 mg of thecompound 4 (0.37 mmol) and Molecular Sieve 4A. With the reactants cooledto 0° C., 195 μL of trimethylsilyl bromide (1.5 mmol) was added,followed by stirring for four hours. A saturated aqueous sodium hydrogencarbonate solution was added to stop the reaction. The reaction mixturewas extracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate and then concentrated. The residues werepurified by silica gel column chromatography (eluent:hexane-toluene=3:7) to obtain the intended compound as yellowishcrystals. (yield: 132 mg(95%))

¹ H NMR (400 MHz): 10.41 (s, 1H), 10.10 (s, 1H), 8.17 (s, 1H), 8.05 (d,J=8.30 Hz, 1H), 7.97 (d, J=8.30 Hz, 1H), 7.85 (d, J=7.81 Hz, 1H), 7.49(t, J=3.42 Hz, 1H), 7.34-7.19 (m, 6H), 7.02-7.00 (m, 3H)

Referential Example 2

Six compounds (6 to 12) represented by the formulae below were prepared.##STR18## wherein LAH represents lithium aluminum hydride, THFrepresents tetrahydrofuran, Et₂ O represents diethyl ether, MsClrepresents mesyl chloride and DMF represents dimethyl formamide.

Synthesis of compound 6

To 120 mL of a tetrahydrofuran solution of 4.5 g of 3,5-dimethylbenzoicacid (30 mmol) was slowly added 1.7 g of lithium aluminum hydride (45mmol), with the temperature kept at 0° C. After refluxing for two hours,8 mL of methanol and 50 mL of 3N hydrochloric acid were added to stopthe reaction. The reaction mixture was extracted with diethyl ether. Theorganic layer was washed successively with a saturated aqueous sodiumhydrogen carbonate solution and a saturated aqueous sodium chloridesolution. The extract was dried over anhydrous magnesium sulfate andthen concentrated. The residues were purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=8:2) to obtain the intendedcompound as colorless oil. (yield: 3.0 g (74%))

Synthesis of compound 7

To 8.60 g of a diethyl ether solution of the compound 6 (63 mmol) wasadded 54.8 g of gamma-manganese oxide (630 mmol), followed by stirringat room temperature for sixteen hours. The reaction mixture was filteredthrough Celite. 8.05 g of the resulting crude product was used as suchfor the subsequent reaction.

Synthesis of compound 8

8.05 g of the crude product (the compound 7) (60 mmol) was dissolved in400 mL of dioxane. To the solution were added 9.9 mL of titaniumtetrachloride (90 mmol) and 11.8 g of zinc dust (180 mmol), bothsuspended in 200 mL of dioxane. After refluxing for four hours, thereaction mixture was partitioned into water and diethyl ether. Theorganic layer was separated and dried over anhydrous magnesium sulfateand then concentrated. The residues were recrystallized from ethanol toobtain the intended compound as colorless crystals. (yield: 3.45 g (48%based on the compound 6))

¹ H NMR (90 MHz): 7.24 (s, 4H), 7.14 (s, 2H), 7.00 (s, 2H), 2.36 (s,12H)

Synthesis of compound 9

A mixture was prepared from 186 mg of hydroquinidine 4-chlorobenzoate(0.4 mmol), 2.96 g of potassium ferricyanide (9.0 mmol), and 1.24 g ofpotassium carbonate (9.0 mmol). To the mixture were successively added20 mL of tertiary butanol, 20 mL of water, 11.1 mg of potassium osmate(VI) dihydrate (0.03 mmol), and 709 mg of the compound 8 (3.0 mmol),followed by stirring at room temperature for twenty four hours. 15 g ofsodium sulfite (0.12 mmol) was added to the resultant, and stirring wascontinued for thirty minutes. After separation into two layers, theaqueous layer was extracted with dichloromethane and the extract wascombined with the organic layer. After concentration, the residues werediluted with ethyl acetate and the solution was washed successively with1M sulfuric acid, a saturated aqueous sodium hydrogen carbonatesolution, and a saturated aqueous sodium chloride solution. The solutionwas dried over anhydrous sodium sulfate and then concentrated. Theresidues were purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1-7:3) to obtain the intended compound ascolorless crystals. (yield: 550 mg (67%))

The compound 9 was found to have an optical purity higher than 99% e.e.,which was determined by the high-performance liquid chromatography thatemploys a chiral column (Daicel Chiralcel OD and eluent ofhexane-isopropanol=15:1).

¹ H NMR (90 MHz): 6.96 (m, 6H), 4.76 (s, 2H), 2.63 (br, s, 2H), 2.30 (s,12H)

Synthesis of compound 10

To 8 mL of a dichloromethane solution of 550 mg of the compound 9 (2.0mmol) were sequentially added 610 μL of triethylamine (4.4 mmol) and 340μL of mesyl chloride (4.4 mmol), followed by stirring at roomtemperature for three hours. The reaction mixture was washed with waterand then concentrated. The residues were purified by silica gel columnchromatography (eluent: diethyl ether) to obtain the intended compoundas colorless crystals. (yield: 839 mg (98%))

¹ H NMR (90 MHz): 6.80-7.10 (m, 6H), 5.74 (s, 2H), 2.86 (s, 6H), 2.23(s, 12H)

Synthesis of compound 11

16 mL of dimethylformamide was added to a mixture of 1.7 g of thecompound 10 (4.0 mmol) and 572 mg of sodium azide (8.8 mmol), followedby stirring at 80° C. for seven hours. The reaction mixture waspartitioned into water and ethyl acetate, and the organic layer wasseparated and dried over anhydrous sodium sulfate and then concentrated.The residues were purified by silica gel column chromatography (eluent:hexane) to obtain the intended compound as colorless crystals. (yield:568 mg (48%))

¹ H NMR (90 MHz): 7.00 (br, s, 2H), 6.84 (br, s, 2H), 4.63 (s, 2H), 2.28(s, 12H)

Example 1 Synthesis of the compound [I-1] of the present invention(Compound 12) ##STR19## wherein EtOH represents ethanol.

32 mg of the compound 11 (0.1 mmol) was dissolved in tetrahydrofuran.7.6 mg of lithium aluminum hydride (0.2 mmol) was added to thetetrahydrofuran solution (1 mL) cooled to 0° C. The mixture was stirredat room temperature for thirty minutes, and 380 μL of a saturatedaqueous potassium fluoride solution (1.59N, 0.6 mmol) was added to stopthe reaction. The reaction mixture was filtered through Celite andextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and then concentrated. The resulting crude product of thecompound 12 and 75.8 mg of the compound 5 (0.2 mmol) were dissolved in 4mL of ethanol, followed by stirring at room temperature for one hour.The reaction mixture was concentrated and added with 24.6 mg ofmanganese acetate tetrahydrate (0.1 mmol) and 4 mL of ethanol, followedby stirring in the air for six hours. The resulting crystals werefiltered off and washed successively with ethanol and then with hexaneto obtain 39.3 mg of the compound [I-1]. The filtrate was concentratedand the residues were recrystallized from dichloromethane-hexane toobtain 7.7 mg of the compound [I-1]. (total yield: 47.0 mg (43% based onthe compound 11))

IR (KBr): 3053, 2920, 1599, 1493, 1425, 1333, 1296, 1223, 1188, 1148,1128, 1045, 1028, 953, 860, 733, 700, 575, 548 cm⁻¹

The same procedure as described above was repeated to obtain thecompound [I-2] to [I-8] of the present invention.

    ______________________________________                                         ##STR20##                     [I]                                            No.    R.sup.1  R.sup.2                                                                             R.sup.3                                                                             R.sup.4                                                                           R      X.sup.-                                                                             Y                                ______________________________________                                        I-1    Ar       H     Ar    H   Ph     AcO.sup.-                                                                           H                                I-2    Ar       H     Ar    H   Ar     AcO.sup.-                                                                           H                                I-3    Ph       H     Ph    H   Ph     AcO.sup.-                                                                           H                                I-4    Ph       H     Ph    H   H      AcO.sup.-                                                                           H                                I-5    Ph       H     Ph    H   Me     AcO.sup.-                                                                           H                                I-6    H        Ph    H     Ph  Me     AcO.sup.-                                                                           H                                I-7    a)       H     a)    H   Ph     AcO.sup.-                                                                           H                                I-8    a)       H     a)    H   Me     AcO.sup.-                                                                           H                                ______________________________________                                         Ar = 3,5dimethylphenyl,                                                       Ph = phenyl,                                                                  AcO.sup.- = CH.sub.3 CO.sub.2.sup.--                                          ##STR21##                                                                

Compound [I-2]

IR (KBr): 3447, 3422, 3049, 3013, 2916, 2680, 1655, 1603, 1558, 1506,1420, 1387, 1333, 1296, 1257, 1223, 1186, 1148, 1117, 1057, 1024, 953,887, 851, 818, 785, 746, 706, 683 cm⁻¹

Compound [I-3]

IR (KBr): 3431, 3053, 1599, 1493, 1443, 1425, 1385, 1333, 1296, 1223,1188, 1148, 1128, 1090, 1072, 1045, 1028, 999, 982, 953, 860, 733, 700,681 cm⁻¹

Compound [I-4]

IR (KBr): 3447, 3422, 3057, 3041, 2928, 1611, 1558, 1491, 1452, 1420,1389, 1342, 1310, 1281, 1229, 1213, 1188, 1150, 1126, 1016, 955, 799,775, 746, 700 cm⁻¹

Compound [I-5]

IR (KBr): 3053, 2922, 2853, 1609, 1555, 1508, 1454, 1423, 1387, 1344,1327, 1300, 1227, 1188, 1148, 810, 746, 702 cm⁻¹ Calcd. for C₆₀ H₄₅ N₂O₄ Mn: C, 78.94; H, 4.97; N, 3.07%. Found: C, 79.80; H, 5.32; N, 3.07%

Compound [I-6]

IR (KBr): 3051, 2920, 1605, 1555, 1508, 1454, 1389, 1344, 1327, 1300,1221, 1188, 1150, 1126, 810, 770, 704, 687 cm⁻¹ Calcd. for C H N OMn.l.5H O:C, 76.67; H, 5.15; N, 2.98% Found: C, 76.50; H, 5.22; N, 3.06%

Compound [I-7]

IR (KBr): 3422, 3053, 2932, 2858, 1609, 1583, 1558, 1493, 1423, 1346,1327, 1223, 1188, 1150, 1124, 1028, 951, 866, 820, 760, 700,658 cm⁻¹

Compound [I-8]

IR (KBr): 3447, 3051, 2936, 2860, 1611, 1583, 1558, 1508, 1489, 1448,1423, 1394, 1346, 1329, 1304, 1273, 1225, 1190, 1169, 1150, 1124, 810,783, 760, 687 cm⁻¹

Example 2-1 Epoxidation of indene ##STR22##

10 μL of indene (86 μmol) was dissolved in 1.1 mL of an acetonitrilesolution of pyridine-N-oxide (0.02M, 22 μmol) and added with 2.3 mg ofthe compound [I-1] (2.1 μmol). To the solution was added 37.8 mg ofiodosylbenzene (0.17 mmol) all at once, followed by stirring at roomtemperature for twenty four hours. The reaction mixture was concentratedand the residues were purified by silica gel column chromatography(eluent: pentane-pentane-diethyl ether=10:1) to obtain the intendedcompound. (epoxide yield: 6.0 mg (53%) (asymmetric yield: 92% e.e.)

Example 2-2 Epoxidation of benzopyran ##STR23##

26.2 mg of compound [IV-1] (0.10 mmol) and 2.6 mg of the compound [I-1](2.5 μmol) were dissolved in 1.25 mL of an acetonitrile solution ofpyridine-N-oxide (0.02M, 0,025 mmol), followed by cooling to 0° C. Tothe resulting solution was added 44.0 mg of iodosylbenzene (0.20 mmol)all at once under a nitrogen atmosphere, followed by stirring at 0° C.for twenty four hours. Insoluble matters were filtered out throughCelite, the filtrate was concentrated, and the residues were purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=8:2-4:6)to obtain the intended compound. (epoxide yield: 20. 1 mg (72%))(asymmetric yield: 98% e.e.) (Daicel Chiralcel OJ,hexane-isopropanol=1:1, flow rate: 0.5 mL/min.)

Example 2-3 Epoxidation of benzopyran ##STR24##

20.0 mg of compound [IV-1] (76.3 μmol) and 1.7 mg of the compound [I-1](1.6 μmol) were dissolved in 760 μL of an acetonitrile solution ofN-methylimidazole (0.02M, 7.6 μmol). To the resulting solution was addeddropwise 86 μL of 30% hydrogen peroxide (0.76 mmol) over five minutes,followed by stirring at room temperature for twenty four hours. Thereaction mixture was concentrated and the residues were purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=1:1) toobtain the intended compound.

(epoxide yield: 7.1 mg (33%) (asymmetric yield: 94% e.e.) (DaicelChiralcel OJ, hexane-isopropanol=1:1, flow rate=0.5 mL/min.)

Example 2-4

The same procedure as described in Example 2-3 was repeated to conductan asymmetric epoxidation on a variety of olefin compounds using thecompound [I] of the present invention as the catalyst by the aid ofiodosylbenzene (PhIO), sodium hypochlorite (NaOCl) or 2-iodosylbenzoicacid (IBA) in acetonitrile. The results are shown in the followingTable.

    __________________________________________________________________________     ##STR25##                                                                    Test No.                                                                           Olefin          Compound [I]                                                                         Yield (%)                                                                           % e. e.                                                                           Abs. confign.                           __________________________________________________________________________     1                                                                                  ##STR26##      I-5    41    68  1S, 2R                                   2                                                                                  ##STR27##      I-6    52    38  1R, 2S                                   3.sup.a)                                                                           ##STR28##      I-5    67    51  1S, 2R                                   4.sup.b)                                                                           ##STR29##      I-5    71    86  1S, 2R                                   5.sup.c)                                                                           ##STR30##      I-5    77    86  1S, 2R                                   6.sup.c)                                                                           ##STR31##      I-3    96    92  1S, 2R                                   7.sup.c)                                                                           ##STR32##      I-5    .sup. .sup.  89.sup.e)                                                                  1S, 2R                                   8.sup.c)                                                                           ##STR33##      I-5    99    89  --.sup.f)                                9.sup.c)                                                                           ##STR34##      I-5    52    91  --.sup.f)                               10.sup.c)                                                                           ##STR35##      I-3    69    98  3R, 5S                                  __________________________________________________________________________     .sup.a) 2-Methylimidazole was added.                                          .sup.b) 4-Dimethylaminopyridine Noxide was added.                             .sup.c) Pyridine Noxide was added.                                            .sup.d) The reaction gave a 3.3:1 mixture of the corresponding cis and        trans epoxides.                                                               .sup.e) The number is the % ee for the cisepoxide. The optical purity of      the transepoxide is 83%.                                                      .sup.f) Absolute. configuration was not determined.                      

    ______________________________________                                         ##STR36##                                                                             Compound                                                             Test No. [I]         Oxidant  Yield(%) % e. e.                                ______________________________________                                         1.sup.a)                                                                              I-1         NaOCl    72       95                                      2.sup.b)c)                                                                            I-1         PhIO     82       94                                      3       I-1         PhIO     52       88                                      4.sup.a)                                                                              I-1         IBA      60       93                                      5       I-2         NaOCl    49       82                                      6.sup.a)                                                                              I-2         NaOCl    69       87                                      7.sup.b)                                                                              I-3         PhIO     70       85                                      8       I-3         NaOCl    51       72                                      9.sup.a)                                                                              I-3         NaOCl    67       95                                     10.sup.a)                                                                              I-4         NaOCl    45       55                                     11.sup.b)                                                                              I-7         PhIO     55       93                                     12.sup.a)                                                                              I-7         NaOCl    72       95                                     13.sup.b)                                                                              I-8         PhIO     60       79                                     14.sup.a)                                                                              I-8         NaOCl    67       93                                     ______________________________________                                         .sup.a) 4-Phenylpyridine was added;                                           .sup.b) Pyridine Noxide was added;                                            .sup.c) -20° C.                                                   

What is claimed is:
 1. An optically active manganese complex of formulaI or I': ##STR37## wherein R¹, R², R³ and R⁴ independently representhydrogen atom, C₁ -C₄ alkyl group, phenyl group which may be substitutedby a halogen atom, C₁ -C₄ alkyl group, C₁ -C₄ alkoxyl group, cyano groupor nitro group; and any two of R¹, R², R³ and R⁴ together form the C₄-C₈ ring,X represents a counter anion which may form a salt, Yrepresents hydrogen atom, halogen atom, C₁ -C₄ alkyl group, C₁ C₁ -C₄alkoxyl group, nitro group or cyano group, R represents hydrogen atom,C₁ -C₄ alkyl group, phenyl group which may be substituted by halogenatom, C₁ -C₄ alkyl group or C₁ -C₄ alkoxyl group, or substituted silylgroup.
 2. A process for producing an optically active epoxy compound offormula III: ##STR38## wherein R⁵ and R⁶ independently represents ahydrogen atom, cyano group, nitro group, amino group which may beprotected by a protecting group, halogen atom, C₁ -C₄ alkyl group, C₁-C₄ alkoxyl group, halo-C₁ -C₄ alkyl group, carboxyl group, formylgroup, C₁ -C₄ alkanoyl group, aroyl group, halo-C₁ -C₄ alkanoyl group,carbamoyl group, C₁ -C₄ alkylsulfinyl group, arylsulfinyl group, C₁ -C₄alkylsulfonyl group, arylsulfonyl group, sulfonamide group, or mono- ordi-C₁ -C₄ alkylsulfonamide group, or if R⁵ and R⁶ are at the orthoposition, R⁵ and R⁶, together with the linking ring, form a group of theformula: ##STR39## wherein n is 0 or an integer of 1, R⁷ represents ahydrogen atom, C₁ -C₄ alkyl group or C₁ -C₄ alkoxy group,R⁸ representsC₁ -C₄ alkyl group or C₁ -C₄ alkoxyl group, R⁷ and R⁸ together form thegroups of the formulae: ##STR40## wherein R⁹, R¹⁰, R¹¹ and R¹²independently represent a hydrogen atom or C₁ -C₄ alkyl group, and theabsolute configuration of the carbon atoms which are marked withasterisks (*) means R or S, comprising asymmetrically epoxidizing anolefin compound of the formula II: ##STR41## wherein R⁵, R⁶, R⁷ and R⁸have the same meanings as defined above, as a starting material, using,as an asymmetric catalyst, an optically active manganese complex of theformula I or I' as claimed in claim 1 to give the compound of theformula III.
 3. A process for producing an optically active benzopyranderivative of formula V: ##STR42## wherein R⁵ and R⁶ independentlyrepresents a hydrogen atom, cyano group, nitro group, amino group whichmay be protected by a protecting group, halogen atom, C₁ -C₄ alkylgroup, C₁ -C₄ alkoxyl group, halo-C₁ -C₄ alkyl group, carboxyl group,formyl group, C₁ -C₄ alkanoyl group, aroyl group, halo-C₁ -C₄ alkanoylgroup, carbamoyl group, C₁ -C₄ alkylsulfinyl group, arylsulfinyl group,C₁ -C₄ alkylsulfonyl group, arylsulfonyl group, sulfonamide group, ormono- or di-C₁ -C₄ alkylsulfonamide group, or if R⁵ and R⁶ are at theortho position, R⁵ and R⁶, together with the linking ring, form a group:##STR43## wherein n means 0 or an integer of 1, R⁹ and R¹⁰ independentlyrepresent hydrogen atom or C₁ -C₄ alkyl group, and the absoluteconfiguration of the carbon atoms which are marked with asterisks (*)means R or S, comprising asymmetrically epoxidizing an olefin compoundof the formula IV: ##STR44## wherein R⁵, R⁶, R⁹ and R¹⁰ have the samemeanings as defined above, using, as an asymmetric catalyst, anoptically active manganese complex of the formula I or I' as claimed inclaim 1 to give the compound of the formula V.
 4. A process forproducing an optically active epoxy derivative of formula VII: ##STR45##wherein R⁹ and R¹⁰ independently represent hydrogen atom or C₁ -C₄ alkylgroup, and the absolute configuration of the carbon atoms which aremarked with asterisks (*) means R or S, comprising asymmetricallyepoxidizing a compound of the formula VI: ##STR46## wherein R⁹ and R¹⁰have the same meanings as defined above, using, as an asymmetriccatalyst, an optically active manganese complex of the formula I or I'as claimed in claim 1, to give the intended compound of the formula VII.5. A process for producing an optically active epoxy derivative offormula IX: ##STR47## wherein the absolute configuration of the carbonatoms which are marked with asterisks (*) means R or S, comprisingasymmetrically epoxidizing an indene compound of the formula VIII:##STR48## as a starting material, using, as an asymmetric catalyst, anoptically active manganese complex of the formula I or I' as claimed inclaim 1, to give the intended compound of the formula IX.